CN107683292A - Specifically bind ERBB3 antibody and application thereof - Google Patents
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Abstract
A kind of specific binding ErbB3 antibody or its antigen-binding fragment and application thereof are provided.Specific binding ErbB3 antibody or its antigen-binding fragment is effectively used for preventing or treats the disease related to the activation of ErbB3 albumen or overexpression.
Description
Technical field
One or more illustrated embodiments are related to a kind of antibody for specifically binding receptor tyrosine kinase ErbB3 albumen
Or antigen-binding fragment, the Its Preparation Method And Use of the antibody.
Background technology
EGF-R ELISA (EGFR or ErbB) family of receptor tyrosine kinase includes ErbB1 (also referred to as epidermises
Growth factor receptors (EGFR)), ErbB2 (also referred to as human epidermal growth factor acceptor (HER2)), ErbB3 (also referred to as HER3)
With ErbB4 (also referred to as HER4).The receptor tyrosine kinase of ErbB families can be by forming homodimer with ligand binding
Or heterodimer and the former activation egg of mitogen original activated protein kinase (MAP2K, MEK or MAPKK)/mitogen can be made
The white signal transduction pathway of kinases (MAPK) or the letter of phosphoinositide -3- kinases (PI3K)/protein kinase B (PKB or Akt)
The activation of number transduction pathway.ErbB protein families are relevant with the generation, development or prognosis of cancer according to reports.
As ErbB1 inhibitor(Cetuximab (Cetuximab)) or(Tarceva (Erlotinib)) and as ErbB2 inhibitor (Herceptin (Trastuzumab)) or(Lapatinib
(Lapatinib)) it is anticarcinogen available on the market.However, many patients are reactionless to these anticarcinogens, and these are anti-
Cancer medicine is with producing drug resistance.In the market not yet obtains ErbB3 or ErbB4 specific inhibitor antibody.
Therefore, it is necessary to develop the genetic diversity that can tackle cancer and overcome new anticancer to the drug resistance of anticarcinogen
Medicine.
The content of the invention
Technical problem
One or more illustrated embodiments include a kind of specific binding ErbB3 antibody or its antigen-binding fragment.
One or more illustrated embodiments include a kind of for preventing or treating and the activation of ErbB3 albumen or overexpression
The pharmaceutical composition of related disease.
One or more illustrated embodiments include it is a kind of prevent or treatment individual in the activation of ErbB3 albumen or crossing table
Up to the method for the disease of correlation.
The solution of problem
This application claims the korean patent application 10-2015- submitted on December 7th, 2015 to Korean Intellectual Property Office
The entire disclosure, is thus herein incorporated by reference by the rights and interests of No. 00173281.
The at large illustrated embodiment shown in refer to the attached drawing, wherein identical reference are referred into phase all the time now
Same key element.In this respect, this illustrated embodiment can have different forms and should not be construed as limitation in this article to
The explanation gone out.Therefore, below by way of referring to the drawings only illustrated embodiment is illustrated to explain each side of this explanation.This
Term "and/or" used herein includes any one of the project of one or more associated listeds or all combined.When statement example
During such as " at least one " before key element list, modify complete key element list and do not modify the individual element of list.
According to the one side of the disclosure, the antigen-binding fragment of the antibody or the antibody that specifically bind ErbB3 includes：
Weight chain variable district, it includes being selected from by sequence number：At least one amino acid sequence in the group of 61 to 85 compositions；
Light chain variable district, it includes being selected from by sequence number：At least one amino acid sequence in the group of 86 to 101 compositions；
Or
The weight chain variable district and the light chain variable district.
There is the heavy chain of five types, represented with γ, δ, α, μ and ε.The type definition of the heavy chain species of antibody.Heavy chain class
Each chains of type α and γ are made up of about 450 amino acid, and each chains of μ and ε are made up of about 550 amino acid.Each heavy chain has two
Individual region, you can become area and constant region.
There is the light chain of two types, represented with λ and κ.Each light chain is made up of about 211 to 217 amino acid.Each mankind
Antibody is containing only a type of light chain.Each light chain contains two continuous fields, including a constant region and a variable region.
Variable region refers to antibody with antigen binding region.
Weight chain variable district may include：Complementarity-determining region-H1 (CDR-H1), it includes being selected from by sequence number：61 to 68 groups
Into group in amino acid sequence；CDR-H2, it includes being selected from sequence number：Amino acid sequence in 69 to 77；And CDR-H3, its
Including selected from sequence number：Amino acid sequence in 78 to 85.For example, the weight chain variable district may include to be selected from by sequence number：1 to 30
Amino acid sequence in the group of composition.Term " complementarity-determining region (CDR) " refers to the position of the variable region of antibody, and the position is assigned
Give the binding specificity of the antibody or its antigen-binding fragment to antigen.
Light chain variable district may include：CDR-L1, it includes being selected from by sequence number：Amino acid sequence in the group of 86 and 87 compositions
Row；CDR-L2, it includes being selected from by sequence number：Amino acid sequence in the group of 88 to 93 compositions；And CDR-L3, it includes being selected from
By sequence number：Amino acid sequence in the group of 94 to 101 compositions.For example, the light chain variable district may include to be selected from by sequence number：31
Amino acid sequence into the group of 60 compositions.
The antibody or its antigen-binding fragment can include weight chain variable district, its be selected from by weight chain variable district CDR-H1,
The group of CDR-H2 and CDR-H3 compositions, the amino acid sequence listed in its expression table 5.
<Table 5>
| Numbering | CDR-H1 | CDR-H2 | CDR-H3 |
| 1 | DYDMS (sequence numbers：61) | SIYPDSGSTYYADSVQG (sequence numbers：69) | DLHMGPEGPFDY (sequence numbers：78) |
| 2 | DYDMS (sequence numbers：61) | TIDLDSGSIYYADSVQG (sequence numbers：70) | DLHMGPEGPFDY (sequence numbers：78) |
| 3 | DYDMS (sequence numbers：61) | SIYPDSGSTDYADSVQG (sequence numbers：71) | DLHMGPEGPFDY (sequence numbers：78) |
| 4 | DYDMS (sequence numbers：61) | SIEPDFGSSYYADSVRG (sequence numbers：72) | DLHMGPEGPFDY (sequence numbers：78) |
| 5 | DYDMS (sequence numbers：61) | IIEPDSGSIYYADSVQG (sequence numbers：73) | DLHMGPEGPFDY (sequence numbers：78) |
| 6 | DYDMS (sequence numbers：61) | SIYPDSGSTDYADSVQG (sequence numbers：71) | DRHMWPEGPFDY (sequence numbers：79) |
| 7 | DYDMS (sequence numbers：61) | SIYPDSGSTYYADSVQG (sequence numbers：69) | DRHMWPEGPFDY (sequence numbers：79) |
| 8 | DYDMS (sequence numbers：61) | SIYPDSGSTYYADSVQG (sequence numbers：69) | DRHMWPEGPFDY (sequence numbers：79) |
| 9 | DYDMS (sequence numbers：61) | SIYPDSGSTYYADSVQG (sequence numbers：69) | DRHMWPEGPFDY (sequence numbers：79) |
| 10 | DYDMS (sequence numbers：61) | TIDLDSGSIYYADSVQG (sequence numbers：70) | DLHMGPEGPFDY (sequence numbers：78) |
| 11 | DYDMS (sequence numbers：61) | TIDLDSGSIYYADSVQG (sequence numbers：70) | DLHMGPEGPFDY (sequence numbers：78) |
| 12 | DYDMS (sequence numbers：61) | SIEPDSGSTDYADSVQG (sequence numbers：74) | DRHMWPEGPFDY (sequence numbers：79) |
| 13 | DYDMS (sequence numbers：61) | TIEPDSGSTYYADSVQS (sequence numbers：75) | DLHMGPEGPFDY (sequence numbers：78) |
| 14 | DYDMS (sequence numbers：61) | SIYPDSGSTYYADSVQG (sequence numbers：69) | DLHMGPEGPFDY (sequence numbers：78) |
| 15 | DYDMS (sequence numbers：61) | SIYPDSGSTDYADSVQG (sequence numbers：70) | DLHMWPEGPFDY (sequence numbers：80) |
| 16 | DYDMS (sequence numbers：61) | TIEPDYGSTLYADSVQG (sequence numbers：75) | DLHMGPEGPFDY (sequence numbers：78) |
| 17 | DYDMS (sequence numbers：61) | GISYDGGNTYYADSVKG (sequence numbers：76) | DPSWCLQDLCYYADGMDV (sequence numbers：81) |
| 18 | WYDMT (sequence numbers：62) | GISYDGGNTYYADSVKG (sequence numbers：76) | DPSWCLQDLCYYADGMDV (sequence numbers：81) |
| 19 | WYDLA (sequence numbers：63) | GISYDGGNTYYADSVKG (sequence numbers：76) | DPSWCLQDLCYYADGMDV (sequence numbers：81) |
| 20 | WYDMS (sequence numbers：64) | GISYDGGNTYYADSVKG (sequence numbers：76) | DPSWCLQDLCYYADGMDV (sequence numbers：81) |
| 21 | WYDIA (sequence numbers：65) | GISYDGGNTYYADSVKG (sequence numbers：76) | DPSWCLQDLCYYADGMDV (sequence numbers：81) |
| 22 | WYDLS (sequence numbers：66) | GISYDGGNTYYADSVKG (sequence numbers：76) | DPSWCLQDLCYYADGMDV (sequence numbers：81) |
| 23 | DYDMS (sequence numbers：61) | AIYYDSGSIYYADSAKG (sequence numbers：77) | DRLFVSDSTFDY (sequence numbers：82) |
| 24 | DYDMS (sequence numbers：61) | AIYYDSGSIYYADSAKG (sequence numbers：77) | DRLFMSDSTFDY (sequence numbers：83) |
| 25 | DYDMS (sequence numbers：61) | AIYYDSGSIYYADSAKG (sequence numbers：77) | DRLFASDSTFDY (sequence numbers：84) |
| 26 | HYDMS (sequence numbers：67) | AIYYDSGSIYYADSAKG (sequence numbers：77) | DRLFASDSTFDY (sequence numbers：84) |
| 27 | YYDMS (sequence numbers：68) | AIYYDSGSIYYADSAKG (sequence numbers：77) | DRLFASDSTFDY (sequence numbers：84) |
| 28 | DYDMS (sequence numbers：61) | AIYYDSGSIYYADSAKG (sequence numbers：77) | DRLFESDSTFDY (sequence numbers：85) |
| 29 | HYDMS (sequence numbers：67) | AIYYDSGSIYYADSAKG (sequence numbers：77) | DRLFESDSTFDY (sequence numbers：85) |
For example, the antibody or its antigen-binding fragment can include weight chain variable district, the weight chain variable district includes：Including sequence
Row number：The CDR-H1 including sequence number of 61 amino acid sequence：The CDR-H2 of 69 amino acid sequence and including sequence number：78
Amino acid sequence CDR-H3.
The antibody or its antigen-binding fragment can include light chain variable district, and the light chain variable district is selected from by light chain variable district
The group of CDR-L1, CDR-L2 and CDR-L3 composition, it includes the amino acid sequence listed in table 6.
<Table 6>
| Numbering | CDR-L1 | CDR-L2 | CDR-L3 |
| 31 | SGSSSNIGSNSVS (sequence numbers：86) | SDNHRPS (sequence numbers：88) | AAWDSSLSGYV (sequence numbers：94) |
| 32 | SGSSSNIGSNSVS (sequence numbers：86) | SDNHRPS (sequence numbers：88) | QGWDTSLSGHV (sequence numbers：95) |
| 33 | SGSSSNIGSNSVS (sequence numbers：86) | SDNHRPS (sequence numbers：88) | AAWDSSLSGYV (sequence numbers：94) |
| 34 | SGSSSNIGSNSVS (sequence numbers：86) | SDNHRPS (sequence numbers：88) | AAWDSSLSGYV (sequence numbers：94) |
| 35 | SGSSSNIGSNSVS (sequence numbers：86) | SDNHRPS (sequence numbers：88) | AAWDSSLSGYV (sequence numbers：94) |
| 36 | SGSSSNIGSNSGS (sequence numbers：87) | ADNWRPS (sequence numbers：89) | AAWDSSLSGYV (sequence numbers：94) |
| 37 | SGSSSNIGSNSGS (sequence numbers：87) | ADNHRPS (sequence numbers：90) | AAWDSSLSGYV (sequence numbers：94) |
| 38 | SGSSSNIGSNSVS (sequence numbers：86) | SDNHRPS (sequence numbers：88) | AAWDSSLSGYV (sequence numbers：94) |
| 39 | SGSSSNIGSNSGS (sequence numbers：87) | ADNWRPS (sequence numbers：89) | AAWDSSLSGYV (sequence numbers：94) |
| 40 | SGSSSNIGSNSVS (sequence numbers：86) | SDNHRPS (sequence numbers：88) | VGWDSSLYGHV (sequence numbers：96) |
| 41 | SGSSSNIGSNSVS (sequence numbers：86) | SDNHRPS (sequence numbers：88) | HAWDSSLWGDV (sequence numbers：97) |
| 42 | SGSSSNIGSNSGS (sequence numbers：87) | ADNWRPS (sequence numbers：89) | AAWDSSLSGYV (sequence numbers：94) |
| 43 | SGSSSNIGSNSVS (sequence numbers：86) | SDNHRPS (sequence numbers：88) | AAWDSSLSGYV (sequence numbers：94) |
| 44 | SGSSSNIGSNSVS (sequence numbers：86) | SDNHRPS (sequence numbers：88) | HAWDSSLYVDV (sequence numbers：98) |
| 45 | SGSSSNIGSNSVS (sequence numbers：86) | ADNFRPS (sequence numbers：91) | AAWDSSLSGYV (sequence numbers：94) |
| 46 | SGSSSNIGSNSVS (sequence numbers：86) | SDNHRPS (sequence numbers：88) | HAWDSSLSGDF (sequence numbers：99) |
| 47 | SGSSSNIGSNSVS (sequence numbers：86) | ADSNRPS (sequence numbers：92) | GSWDYSLSGYV (sequence numbers：100) |
| 48 | SGSSSNIGSNSVS (sequence numbers：86) | ADSNRPS (sequence numbers：92) | GSWDYSLSGYV (sequence numbers：100) |
| 49 | SGSSSNIGSNSVS (sequence numbers：86) | ADSNRPS (sequence numbers：92) | GSWDYSLSGYV (sequence numbers：100) |
| 50 | SGSSSNIGSNSVS (sequence numbers：86) | ADSNRPS (sequence numbers：92) | GSWDYSLSGYV (sequence numbers：100) |
| 51 | SGSSSNIGSNSVS (sequence numbers：86) | ADSNRPS (sequence numbers：92) | GSWDYSLSGYV (sequence numbers：100) |
| 52 | SGSSSNIGSNSVS (sequence numbers：86) | ADSNRPS (sequence numbers：92) | GSWDYSLSGYV (sequence numbers：100) |
| 53 | SGSPSNIGNNSVT (sequence numbers：87) | YDSHRPS (sequence numbers：93) | GSWDASLNGYV (sequence numbers：101) |
| 54 | SGSPSNIGNNSVT (sequence numbers：87) | YDSHRPS (sequence numbers：93) | GSWDASLNGYV (sequence numbers：101) |
| 55 | SGSPSNIGNNSVT (sequence numbers：87) | YDSHRPS (sequence numbers：93) | GSWDASLNGYV (sequence numbers：101) |
| 56 | SGSPSNIGNNSVT (sequence numbers：87) | YDSHRPS (sequence numbers：93) | GSWDASLNGYV (sequence numbers：101) |
| 57 | SGSPSNIGNNSVT (sequence numbers：87) | YDSHRPS (sequence numbers：93) | GSWDASLNGYV (sequence numbers：101) |
| 58 | SGSPSNIGNNSVT (sequence numbers：87) | YDSHRPS (sequence numbers：93) | GSWDASLNGYV (sequence numbers：101) |
| 59 | SGSPSNIGNNSVT (sequence numbers：87) | YDSHRPS (sequence numbers：93) | GSWDASLNGYV (sequence numbers：101) |
| 60 | SGSPSNIGNNSVT (sequence numbers：87) | YDSHRPS (sequence numbers：93) | GSWDASLNGYV (sequence numbers：101) |
For example, the antibody or its antigen-binding fragment can include light chain variable district, the light chain variable district includes：Including sequence
Row number：The CDR-L1 including sequence number of 86 amino acid sequence：The CDR-L2 of 88 amino acid sequence and including sequence number：94
Amino acid sequence CDR-L3.
ErbB3 can be ErbB3 polypeptides or its fragment.ErbB3 polypeptides can be that GenBank accesses numbering NP_
001005915 human amino acid sequence or GenBank access numberings NP_034283 mouse amino acid sequence.ErbB3 is more
The fragment of peptide can be polypeptide, and the polypeptide includes the partial amino-acid series of ErbB3 polypeptides.ErbB3 is epidermal growth factor receptor
The receptor tyrosine kinase of body (EGFR or ErbB) family, and also referred to as HER3.
The antibody or its antigen-binding fragment for specifically binding ErbB3 can be with the parents to ErbB3 polypeptides or its fragment
And property.
The antibody or its antigen-binding fragment can suppress material of the ErbB3 albumen with specifically binding ErbB3 albumen
With reference to, ErbB1 albumen and the dimerization of ErbB3 albumen, dimerization, ErbB2 albumen and the ErbB3 eggs of ErbB1 albumen and ErbB3 albumen
White dimerization, ErbB3 or Akt phosphorylation or its combination.The material for specifically binding ErbB3 albumen can be heregulin
(heregulin)(HRG)。
Term " antibody " is used interchangeably with " immunoglobulin (Ig) ".Entirely antibody, which has, includes 2 full-length light chains and 2
The structure of individual total length heavy chain (by double sulphur (SS) key connection).Antibody can be such as IgA, IgD, IgE, IgG or IgM.Antibody can
Think monoclonal antibody or polyclonal antibody.Antibody can be anti-for the antibody from animal, mouse-human chimeric's antibody, peopleization
Body or human antibodies.
Term " antigen-binding fragment " refers to the fragment of whole immunoglobulin structure, and it can be to include antigen-binding portion
A part for the polypeptide of position.For example, the antigen-binding fragment can be scFv, (scFv)2、Fv、Fab、Fab'、Fv F(ab')2、
Or its combination.
The antibody or its antigen-binding fragment can be modified.For example, the antibody or its antigen-binding fragment can pass through
Conjugated (conjugation) or combination, candy base, label attachment (tag attachment) or its combination are modified.This is anti-
Body can be conjugated with other drugs such as anticarcinogen.For example, the antibody or its antigen-binding fragment can be conjugated with following：Horseradish
Peroxidase (HRP), alkaline phosphatase, haptens, biotin, streptavidin (streptavidin), fluorescent material, radiation
Property material, quantum dot, polyethylene glycol (PEG), it is histidine-tagged or its combination.Fluorescent material can be Alexa
532、Alexa 546、Alexa 568、Alexa 680、Alexa 750、
Alexa 790 or Alexa FluorTM350。
According to another aspect of the present disclosure, for preventing or treating the disease related to the activation of ErbB3 albumen or overexpression
The pharmaceutical composition of disease includes the antibody or its antigen-binding fragment according to any of the above-described illustrated embodiment.
The antibody, antigen-binding fragment and ErbB3 albumen are same as described above.
Activation to ErbB3 albumen or to be overexpressed related disease can be cancer.Cancer can be solid carcinoma or non-reality
Body cancer.Solid carcinoma refers to that cancerous tumour is fallen ill in solid organ for example in liver, lungs, breast or skin, rather than solid carcinoma is
Referring to influences the cancer of blood, therefore referred to as leukemia.For example, cancer can be selected from consisting of the following group：Breast cancer, cutaneum carcinoma, head
Neck cancer, cancer of pancreas, lung cancer, colon cancer, colorectal cancer, stomach cancer, oophoroma, prostate cancer, carcinoma of urinary bladder, uterine cancer, liver cancer,
Renal cancer, clear cell sarcoma, melanoma, myelencephalon tumour, the cancer of the brain, thymoma, celiothelioma, cancer of the esophagus, cancer of bile ducts, testis
Cancer, embryo cancer (germinal cancer), thyroid cancer, parathyroid carcinoma, cervix cancer, carcinoma of endometrium, lymthoma, marrow
Hyperplasia exception syndrome (MDS), myelofibrosis, acute leukemia, chronic leukemia, Huppert's disease, Hodgkin's disease,
Endocrine cancer and sarcoma.
Term " prevention " refers to suppress or postpone and the activation of ErbB3 albumen or mistake table by giving the pharmaceutical composition
Up to any behavior of the seizure of disease of correlation.Term " treatment " refers to make and ErbB3 albumen by giving the pharmaceutical composition
Activation or be overexpressed related disease symptom mitigation any behavior.
The pharmaceutical composition can include pharmaceutically acceptable supporting agent.Supporting agent is appreciated that it means excipient, dilution
Agent or adjuvant.For example, carrier can be selected from consisting of the following group：Lactose, dextrose, sucrose, D-sorbite, mannitol,
Xylitol, antierythrite, maltitol, starch, acacin, alginates, gelatin, calcium phosphate, calcium silicates, cellulose, methyl
Cellulose, PVP, water, physiological saline, buffer such as phosphate buffered saline (PBS) (PBS), hydroxybenzoic acid
Methyl esters, nipasol, talcum, magnesium stearate, glycine, histidine, serine, polysorbate and mineral oil.
The pharmaceutical composition can include filler, anti-coagulants, lubricant, wetting agent, flavor enhancement, emulsifying agent, preservative or its combination.
The pharmaceutical composition can use any commonly employed method in this area to be deployed into any form.For example, the medicine group
Compound can be deployed into oral dose shape (for example, powder, lozenge, capsule, syrup, pill or particle) or parenteral dose shape
(such as injection).The pharmaceutical composition can be prepared into preparation or formulations for topical administration for systemic applications.
The pharmaceutical composition may further include anticarcinogen.Anticarcinogen can be Cetuximab (Cetuximab), pa
Buddhist nun's monoclonal antibody (Panitumumab), Tarceva (Erlotinib), Gefitinib (Gefitinib), Herceptin
(Trastuzumab), T-DM1, handkerchief trastuzumab (Pertuzumab), Lapatinib (Lapatinib), taxol, tamoxifen
Fragrant (Tamoxifene), cis-platinum, anti-CTLA-4 antibody, anti-PD-1 antibody, anti-PDL-1 antibody, 5 FU 5 fluorouracil (5FU), Ji
His shore (Gemcitabine) of west or its combination.The pharmaceutical composition can include single composition or discrete (separate) group
Compound.For example, the antibody of the pharmaceutical composition or its antigen-binding fragment can be the composition of parenteral dose shape and resist
Cancer medicine can be the composition of oral dose shape.
The pharmaceutical composition can include the antibody or its antigen-binding fragment, the anticarcinogen or its combination of effective dose.This
Term " effective dose " used herein refer to when deliver medicine to needs this prevention or treatment individual when be enough to prevent or treat and
The activation of ErbB3 albumen or the amount for being overexpressed related disease.Effective dose can be by those of ordinary skill in the art according to selection
Cell or individual properly select.For example, effective dose can depend on disease severity, the age of patient, body weight, health
Situation, sex, patient drug susceptibility, administration the duration, method of administration, excretion rate, treatment the duration and other because
Element and suitably determine, other factors include combine with the pharmaceutical composition or used simultaneously in medicine and medical field
The other factors known.Effective dose can be about 0.5 μ g to about 2g, about 1 μ g to about 1g, about 10 μ g to about
500mg, about 100 μ g to about 100mg or about 1mg to about 50mg pharmaceutical composition.
When delivering medicine to adult, the dosage of the pharmaceutical composition can be such as about 0.001 ㎎/kg to about 100 ㎎/
Kg, about 0.01 ㎎/kg to about 10 ㎎/kg or about 0.1 ㎎/kg to about 1 ㎎/kg.The quantity of administration can be exemplified by
As once or several times a day, weekly, two weeks once, once in three weeks, surrounding once or annually.
According to another aspect of the present disclosure, the activation to ErbB3 albumen or overexpression are related in vivo for prevention or treatment
The method of disease includes the antibody according to any of the above-described illustrated embodiment or its antigen-binding fragment delivering medicine to the individual.
It is the antibody, antigen-binding fragment, ErbB3 albumen, the disease related to the activation of ErbB3 albumen or overexpression, pre-
Anti- or treatment can be with same as described above.
Individual can be mammal, such as the mankind, cow, horse, pig, dog, sheep, goat or cat.Individual can be to suffer from
There is the individual of the disease related to the activation of ErbB3 albumen or overexpression or be susceptible to suffer from the individual of the disease, the disease can be
Cancer.
This method may further include delivers medicine to the individual by anticarcinogen.Anticarcinogen can with according to any of the above-described illustration
The antibody of embodiment or its antigen-binding fragment simultaneously, dividually or are one after the other administered.
For example, the antibody or its antigen-binding fragment, anticarcinogen or its combination can be directly administered by any method in
The individual, such as pass through oral, intravenous, intramuscular, percutaneous, mucous membrane, intranasal, tracheal strips or subcutaneous administration.The antibody or its
Antigen-binding fragment, anticarcinogen or its combination can systemically or topically be administered.The antibody or its antigen-binding fragment, anticarcinogen
Or its combination can be administered individually or together with pharmaceutical active compounds.
Dosage of the antibody or its antigen-binding fragment, anticarcinogen or its combination can depend on the situation of patient, body weight,
Disease severity, pharmaceutical preparation, method of administration and administration duration and change, and can be by those of ordinary skill in the art
Properly select.For example, when delivering medicine to adult, the dosage of the antibody or its antigen-binding fragment, anticarcinogen or its combination can
Think about 0.001 ㎎/kg to about 100 ㎎/kg, about 0.01 ㎎/kg to about 10 ㎎/kg or about 0.1 ㎎/kg
To about 1 ㎎/kg.The quantity of administration can be for example once or several times a day, weekly, two weeks once, once in three weeks, four
Zhou Yici or annually.
According to another aspect of the present disclosure, the method for prevention or the internal cancer drug drug resistance for the treatment of includes will by right
Any one of 1 to 10 antibody or antigen-binding fragment is asked to deliver medicine to the individual.
Brief description of the drawings
From the explanation below in conjunction with accompanying drawing to illustrated embodiment, these and/or other aspect will be apparent and more hold
It is readily understood, wherein：
Fig. 1 a and Fig. 1 b represent heavy chain (Fig. 1 a) and the light chain (figure of antibody lead (lead antibody) and its modified antibodies
The amino acid sequence and complementarity-determining region (CDR) in variable region 1b)；
Fig. 2 is the figure for representing ErbB3 albumen and HRG binding affinity (%) in the presence of anti-ErbB3 antibody；
Fig. 3 binding affinities of ErbB2 albumen and ErbB3 albumen (%) in the presence of anti-ErbB3 antibody for expression
Figure；
Fig. 4 a and 4b are the figure for being illustrated respectively in ErbB3 and Akt phosphoric acid rate (%) in the presence of anti-ErbB3 antibody；
Fig. 5 is the figure of the relative propagation (%) of BxPC3 pancreatic cancer cells in the presence of anti-ErbB3 antibody；
Fig. 6 is the gross tumor volume (mm in BT474 breast cancer heteroplastic transplantation models after giving anti-ErbB3 antibody3) figure；
Fig. 7 is the gross tumor volume (mm in MDA-MB-468 breast cancer heteroplastic transplantation models after giving anti-ErbB3 antibody3)
Figure；
Fig. 8 is the gross tumor volume (mm in A431 cutaneum carcinoma heteroplastic transplantation models after giving anti-ErbB3 antibody3) figure；
Fig. 9 is to give anti-ErbB3 antibody or FaDu incidences after anti-ErbB3 antibody and Cetuximab are given in combination
Gross tumor volume (mm in cancer heteroplastic transplantation model3) figure；
Figure 10 is that Caspase-3/7 in breast cancer cell are given after taxol, HRG and anti-ErbB3 antibody in combination
The figure of the activity (in terms of relative luminance unit (RLU)) of (caspase 3/7)；
Figure 11 is that combination is given cancer cell in Cetuximab, HRG and anti-ErbB3 antibody postcolon rectum cancer cell and increased
Grow rate (%) figure；And
Figure 12 is that combination is given after Cetuximab and anti-ErbB3 antibody in the heteroplastic transplantation model of resistance to Cetuximab
The figure of gross tumor volume.
Embodiment
One or more embodiments of the disclosure are explained hereinafter with reference to the following example.However, these
Embodiment is only intended to illustrate and is not intended to the scope of one or more embodiments of the limitation disclosure.
The preparation of the anti-ErbB3 antibody of embodiment 1.
1. the screening of antibody lead
In order to obtain the anti-ErbB3 antibody of the mankind, the mankind synthesize scFv- phage display libraries (by pear flower woman university of South Korea
H.B.SHIM provide) ErbB3 albumen (R＆D systems) is screened, to obtain the scFv pieces that are combined with ErbB3 of displaying
The bacteriophage of section.
The nucleotide sequence of the scFv fragments of the bacteriophage obtained to coding is analyzed, and passes through amino acid sequence analysis
The amino acid sequence of the VH and VL domains for the scFv fragments for combining ErbB3 is recognized.Obtain the scFv pieces with reference to ErbB3
After the sequence of section, VH and VL domains are recombinated using the coding IgG1 carriers of Selexis 085 (Selexis), thus set up
Whole antibody gene.The expression vector for the restructuring for encoding IgG1 is turned into shape and to be expressed in Chinese hamster ovary on a small scale
(CHO) in cell line.The anti-ErbB3 antibody of expression the measure and cell base of ErbB3 binding affinity are analyzed,
Thus anti-ErbB3 antibody leads 442P, 472P and 451P are screened, it suppresses heregulin (HRG)-dependence ErbB3 signal transductions.
2. screen modified antibodies from antibody lead
Fab- phage display libraries induce by using random mutation to be mutated the anti-of the screening of introducing embodiment 1.1
ErbB3 antibody leads 442P, 472P and 451P six CDR positions and built.Fab- phage display libraries are by using customization
Primer and Phusion polymerases (New England (are manufactured) by Integrated DNA Technologies, Inc.
Biolabs), expanded by polymerase chain reaction (PCR).
By the Fab- phage display libraries of structure for recombinant human ErbB3 albumen (R＆D systems) screened with
Screen has the antibody of improved binding affinity compared with antibody lead to recombinant human ErbB3.The antibody of screening such as embodiment
IgG is reassembled as described in 1.1 and turns shape and to be expressed on a small scale in Chinese hamster ovary celI system.
UtilizeQK384 systems (Pall Life Sciences) determine the binding affinity of anti-ErbB3 antibody.
The antibody compared with antibody lead with improved binding affinity is screened according to result, and carries out the analysis of cell base to verify
Efficiency.The amino acid sequence of the variable region of anti-ErbB3 antibody leads and modified antibodies is analyzed, and is determined according to Kabat definition
Complementarity-determining region (CDR).Amino acid sequence (the sequence in the heavy chain of the antibody of screening and each region of light chain is shown in Fig. 1 a and 1b
Row number：1 to 60) amino acid sequence in the CDR of heavy chain and light chain, and in table 1 and 2 is shown respectively.
【Table 1】
【Table 2】
The in vitro effect of the anti-ErbB3 antibody of embodiment 2.
1. the binding affinity of anti-ErbB3 antibody on human class ErbB3 albumen
Determine binding affinity of the antibody (embodiment 1.2) to ErbB3 albumen (antigen) of screening.
Specifically, anti-ErbB3 antibody is to the binding affinity of recombinant human ErbB3 albumen (R＆D systems) and anti-
Antigen-antibody interaction dynamics by usingQK384 systems (Pall Life Sciences) determine.
1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochloride (EDC) of 20mM on AR2G sensors (ForteBio)
And after the activation of the carboxyl in 40mM NHS (sulfo group-NHS) solution, addition 10mM sodium acetate
(pH 4.0) (ForteBio) dilution 10 μ g/mL mankind ErbB3 protein solutions so that mankind's ErbB3 proteopexies in AR2G
On sensor.Make mankind ErbB3 proteopexies to AR2G sensors and handled with 1M monoethanolamine (ForteBio) so that surplus
Remaining unreacted carboxyl inactivation.12.5nM, 25nM and 50nM antibody-solutions are each added on AR2G sensors, then observed
The combination of reaction product mutually about 900 seconds.Then, 1x dynamics buffer solution (ForteBio) is added into reaction product, and
The dissociation of observing response product mutually about 1200 seconds, is then usedAnalysis software (Sciences) really
Association constant (ka), dissociation constant (kd) and the equilibrium dissociation constant (KD) of fixed each antibody-like.
【Table 3】
Referring to table 3, finding the antibody of selection has about 0.1nM to about 0.1pM equilibrium dissociation constant (KD), represents
The binding affinity high to recombinant human ErbB3 albumen.
2. the ErbB3 albumen-HRG of anti-ErbB3 antibody combines rejection ability
Whether the antibody for investigating the selection of embodiment 1.2 suppresses ErbB3 albumen and the HRG as its part combination.
Specifically, HRG (R＆D systems) utilizes to the binding affinity of mankind ErbB3 albumen (R＆D systems)QK384 systems (Pall Life Sciences) are determined.According to the same procedure used in such as embodiment 2.1
Make 10 μ g/mL HRG proteopexies after on AR2G sensors, make remaining unreacted carboxylic using 1M monoethanolamines (ForteBio)
Base inactivates.Then, 5 μ g/mL mankind ErbB3 albumen (R＆D systems) and 10nM or 100nM anti-ErbB3 antibody are added
Mixed solution to being fixed with thereon on the Ar2G sensors of HRG albumen, then observation combine mutually about 900 seconds.Using not having
The reaction product of anti-ErbB3 antibody is added as negative control group.The HRG albumen that measure is fixed on AR2G sensors is combined
Remaining mankind ErbB3 albumen amount.ErbB3 albumen and HRG are calculated in the presence of anti-ErbB3 antibody relative to negative right
According to the binding affinity (%) of group.As a result shown in Figure 2, wherein Y-axis represents the binding affinity relative to negative control group
(%), and X-axis represents various concentrations 0nM, 10nM and 100nM antibody.
Referring to Fig. 2, it is found that the antibody of selection suppresses the combination of mankind ErbB3 albumen and HRG albumen according to the concentration of antibody,
And hIgG control groups show that the combination for ErbB3 and HRG does not have effect.
3. the ErbB2-ErbB3 dimerization rejection abilities of anti-ErbB3 antibody
Investigated and suppress ErbB2 albumen and the energy of the dimerization of ErbB3 albumen to assess the antibody of the selection of embodiment 1.2
Power.
Specifically, by 100Recombinant human ErbB2 albumen (1 μ g/mL) be applied to more orifice plate (Thermo of array 96
Scientific) and at 4 DEG C cultivate about 16 hours so that the coating of ErbB2 albumen is at most on the orifice plate of array 96.By 2005% (w/v) BSA/PBS solution be applied to the plate of coating and cultivated at 37 DEG C about 1 hour.By 50Recombined human
Class ErbB3 albumen (0.6 μ g/mL) and 50Selection anti-ErbB3 antibody (0.2 μ g/mL) mixture be applied to plate and
Reactant mixture is cultivated about 2 hours at 37 DEG C.Obtained plate is cleaned three with 0.05% (v/v) Tween/PBS solution
It is secondary.By 100Goat-anti-ErbB3 polyclonal antibodies (1 μ g/mL, R＆D systems) be applied to cleaning plate and
Cultivated at 37 DEG C about 1 hour.Then with 0.05% (v/v) Tween/PBS solution clean plate three times.5% (w/v) BSA/ will be used
PBS solution is with 1:The 100 of 5000 dilutionsAnti- goat Fc- horseradish peroxidases (HRP) (Jackson
Immunoresearch plate) is applied to, is then cultivated about 1 hour in 37 DEG C.Then it is molten with 0.05% (v/v) Tween/PBS
Liquid cleans plate three times.Using as the 100 of matrix3,3', 5,5'- tetramethyl benzidines (TMB) be applied to each hole and
Cultivate at room temperature about 5 minutes, then with 1002N sulfuric acid solutions make reaction terminating.Use no anti-ErbB3 of addition
The reactant mixture of antibody is as negative control group.Absorbance of the assay plate under 450nm wavelength.Calculated from the absorbance measured
The binding affinity of ErbB2 albumen and ErbB3 albumen in the presence of anti-ErbB3 antibody.Use the mankind not combined with ErbB3
IgG is as another negative control group.
ErbB2 albumen and ErbB3 albumen are calculated in the presence of anti-ErbB3 antibody relative to the combination of negative control group
Compatibility (%).As a result shown in Figure 3, wherein Y-axis represents the binding affinity (%) relative to negative control group, and hIgG
Represent IgG.
Referring to Fig. 3, it is found that the antibody of selection suppresses the dimerization of ErbB2 albumen and ErbB3 albumen, and hIgG control groups do not have
Any dimerization is shown to suppress.
4. the ErbB3 and Akt phosphorylation rejection ability of anti-ErbB3 antibody
Investigated to assess the ability that the antibody of the selection of embodiment 1.2 suppresses ErbB3 albumen and Akt phosphorylation.
Specifically, about 5x10 is made5Individual MCF7 breast cancer cells (coming from National Institutes of Health) connect
On kind to 24 orifice plates, and addition includes Pen .- Strep antibiotic (Invitrogen) and 10% (v/v) hyclone
(FBS) on culture medium (Invitrogen) to 24 orifice plates of Roswell Park Memorial Institute (RPMI) -1640
Cell, and in 5%CO2Under the conditions of, 37 DEG C cultivate about 24 hours.Then, culture medium is changed into fresh RPMI-
1640 culture mediums, and culture cell about 24 hours under the conditions of serum starvation.Then, the anti-ErbB3 antibody of selection is added
Add to cell and in 5%CO2Under the conditions of, 37 DEG C cultivate about 2 hours.By antibody 442P antibody and 472P with about
67nM, 13nM, 3nM, 534pM, 107pM, 21pM and 4pM concentration are each added to cell, and by antibody 442S1,442S5,
442M6 and 472S2 is added to cell with 13nM, 3nM, 834pM, 208pM, 52pM and 13pM concentration.At 45 minutes 1 hour
Afterwards, HRG is added to cell and in 5%CO2Under the conditions of, cultivate at 37 DEG C about 15 minutes to stimulate cell (at total antibody
Manage the time：2 hours).By the PBS of cell cooling and add lysing solution (Cell Signaling
Technology) thus to collect cell.Carried out by BCA analyses the intracellular protein of selection it is quantitative after, analysis
ErbB3 or Akt phosphorylation level.
Use Phospho-ErbB3 detection kits (Cell Signaling Technology) analysis ErbB3 phosphoric acid
Change horizontal.After cell protein is bound to the elisa plate of ErbB3 antibody-coating, phosphotyrosine is made on elisa plate
(phosphotyrosine) the anti-mouse antibody development (develop) that mouse detection antibody and HRP- are conjugated.Then, four are added
Methyl biphenyl amine (TMB) matrix stops reaction, and surveyed with plate reader to reaction product with the reacting terminating solution of kit
Determine absorbance.
Use Phospho-Akt1 detection kits (Cell Signaling Technology) analysis Akt1 phosphorylation
It is horizontal.After cell protein is bound to the elisa plate of anti-phosphoserine (phosphoserine)-coating, in elisa plate
On Akt1- specific detection antibodies and HRP- conjugation of antibodies is developed.Then, after the reaction with TMB matrix, with kit
Reacting terminating solution stops reaction, and determines absorbance with plate reader.
Fig. 4 a and 4b are the figure drawn based on the absorbance measured, and it is respectively the ErbB3 and Akt relative to antibody concentration
Phosphoric acid rate figure.Half maximum suppression concentration (IC of calculating antibody50).As a result it is shown in Table 4.
【Table 4】
Referring to Fig. 4 a and 4b and table 4, it is found that the antibody of selection suppresses ErbB3 and Akt phosphorylation.
Similarly, it has been found that the antibody of selection suppress following in ErbB3 and Akt phosphorylation：Breast cancer cell line MDA-
MB-468 and BT474, skin cancer cell system A431, pancreatic carcinoma BxPC3, incidence cancer cell line FaDu, lung carcinoma cell
It is A549, colorectal cancer cell system LoVo, K-1735 MALME-3M, ovarian cancer cell line OVCAR-8 and preceding
Row gland cell system DU145.
5. the pancreatic carcinoma BxPC3 Proliferation Ability abilities of anti-ErbB3 antibody
Investigated to assess the ability that the antibody of the selection of embodiment 1.2 suppresses BxPC3 Cell Proliferation of Pancreatic Cancer Cell.
Specifically, will about 1x104Individual BxPC3 pancreatic cancer cells (American Type Culture Collection)
Be seeded on 96 orifice plates, and add include it is thin on 10%FBS RPMI-1640 culture mediums (Invitrogen) to 96 orifice plates
Born of the same parents, and in 5%CO2Under the conditions of, cultivated at 37 DEG C about 24 hours.Then, culture medium is changed into including 0.1% (v/v)
FBS RPMI-1640 culture mediums.Add 0.02 μ g/mL, 0.2 μ g/mL, 2 μ g/mL and 20 μ g/mL 442S1 antibody or 442M6
Antibody is to the cell cultivated and in 5%CO2Under the conditions of, cultivated at 37 DEG C about 2 hours.Further add 50ng/mL's
The cell that HRG is extremely cultivated, and in 5%CO2Under the conditions of, cultivated at 37 DEG C about 120 hours.Use no addition antibody
The cell of culture is as negative control group.Use CellTiter-Glo luminescent cell viability analytic approach (CellTiter-Glo
Luminescent Cell Viability Assay) (Promega) measure living cells number.Counted based on the result measured
Calculate relative proliferation rate.As a result it is shown in Fig. 5.
Referring to Fig. 5, it is found that the antibody of selection suppresses the propagation of BxPC3 pancreatic cancer cells in a manner of concentration dependant.
The in vivo effect of the anti-ErbB3 antibody of embodiment 3.
1. use the Tumor growth inhibition of BT474 breast cancer heteroplastic transplantation models
Investigated and suppress tumour in breast cancer cell animal xenografts model to assess the antibody of the selection of embodiment 1.2
The ability of growth.
Specifically, human breast cancer BT474 cells (American Type Culture Collection) are incubated at bag
In Dulbecco's Modified Eagle's medium (DMEM) culture mediums (Hyclone) for including 10%FBS.In cancer cell
The previous day is inoculated with by 17 beta estradiols-slow-release pill (0.36mg/60 days, Innovative Research of America) skin
Under be seeded in female NOD/SCID mouse (HFKBio-Technology Co.Ltd.) to maintain the estrogen level of blood.
Make about 1x107Individual BT474 cancer cells are suspended in 100 containing 50%MatrigelPBS in, and by the cancer cell of suspension
It is injected in the inframammillary adipose tissue of every mouse.The weight of one week measure mouse is secondary, and utilizes " 0.5a xb2"
Equation calculates gross tumor volume, and wherein a and b is respectively the major diameter and minor axis of tumour.Gross tumor volume after cancer cell inoculation 7 days
Reach about 210mm3When, mouse is randomly assigned into 7 groups, every group includes 10 mouse., will with the dosage of 10mg/kg body weight
PBS (negative control group), antibody 442P, 442S1,442S5,442M6,472S2 and 472M1 are administered to the tail of the mouse in each group
In vein one week it is secondary, last 4 weeks.After being inoculated with cancer cell, the gross tumor volume after antibody is given in calculating.As a result it is shown in Fig. 6.
Referring to Fig. 6, find relative to negative control group, reduce gross tumor volume by giving antibody, and select
Antibody inhibiting tumor grows.
2. use the Tumor growth inhibition of MDA-MB-468 breast cancer heteroplastic transplantation models
By human breast cancer cells MDA-MB-468 (American Type Culture Collection) in including 10%
(v/v) cultivated in the L-15 culture mediums (Hyclone) of hyclone.Make about 5x106Individual cancer cell is suspended in including 50%
The 100 of MatrigelPBS in, and be subcutaneously injected to female Nu/Nu mouse (Vital River laboratories,
Ltd in subventral space).The weight of one week measurement mouse is secondary, and utilizes " 0.5a x b2" equation calculate tumour body
Product, wherein a and b are respectively the major diameter and minor axis of tumour.Gross tumor volume reaches about 210mm after cancer cell injection 7 days3When,
Mouse is randomly assigned into 7 groups, every group includes 10 mouse.With the dosage of 10mg/kg body weight by PBS (negative control group), anti-
Body 442P, 442S1,442S5,442M6,472S2 and 472M1 be administered in the tail vein of each group mouse one week it is secondary, last 4
Week.After cancer cell is inoculated with, the gross tumor volume after antibody is given in calculating.As a result it is shown in Fig. 7.
Referring to Fig. 7, find relative to negative control group, reduce gross tumor volume by giving antibody, and select
Antibody inhibiting tumor grows.
3. use the Tumor growth inhibition of A431 cutaneum carcinoma heteroplastic transplantation models
By human skin cancer A431 cells (American Type Culture Collection) in including 10%FBS's
Cultivated in DMEM culture mediums (Hyclone).Make about 5x106Individual cancer cell is suspended in 100 including 50%Matrigel's
In PBS and it is subcutaneously injected to female Balb/c nude mices (HFKBio-Technology Co.Ltd.) subventral space.Survey within one week
It is secondary to determine the weight of mouse, and utilizes " 0.5a x b2" equation calculate gross tumor volume, wherein a and b is respectively tumour
Major diameter and minor axis.Gross tumor volume reaches about 160mm after cancer cell inoculation 7 days3When, mouse is randomly assigned into 7 groups, often
Group includes 10 mouse.With the dosage of 10mg/kg body weight by PBS (negative control group), antibody 442P, 442S1,442S5,
442M6,472S2 and 472M1 be administered in the tail vein of each group mouse one week it is secondary, last 4 weeks.After cancer cell is inoculated with, meter
The gross tumor volume after antibody is given in calculation.As a result it is shown in Fig. 8.
Referring to Fig. 8, find relative to negative control group, reduce gross tumor volume by giving antibody, and select
Antibody inhibiting tumor grows.
4. use the Tumor growth inhibition of Tumor Xenograft Models
In a manner of with the identical in embodiment 2.1 to 2.3, antibody 442S1 is administered to FaDu incidence cancers, pancreas
In cancer or lung cancer animal models, and by antibody 442P or 472P antibody administration into animal modal of gastric carcinoma.As a result find relative
In negative control group, reduce gross tumor volume by giving antibody, and the antibody inhibiting tumor growth selected.
The effect of the combination medicine-feeding of the anticarcinogen of embodiment 4. and anti-ErbB3 antibody
Investigated is improved with assessing antibody 442S1 and being combined in FaDu incidence cancer models for Cetuximab
The ability of anticancer effect.
Mankind incidence cancer FaDu cells (Shanghai Institutes for Biological Sciences) are existed
Cultivated in EMEM culture mediums (Hyclone) including 10%FBS.Make about 5x106Individual cancer cell is suspended in including 50%
The 100 of MatrigelPBS in and be subcutaneously injected to female NOD/SCID mouse (HFK Bio-Technology
Co.Ltd in subventral space).The weight of one week measure mouse is secondary, and utilizes " 0.5a x b2" equation it is swollen to calculate
Knurl volume, wherein a and major diameter and minor axis that b is respectively tumour.Gross tumor volume reaches about 150mm after cancer cell inoculation 7 days3
When, mouse is randomly assigned into 7 groups, every group includes 10 mouse.With the dosage of 5mg/kg body weight by PBS (negative control group),
Antibody 442S1 and Cetuximab (Merck) be administered in the tail vein of each group mouse one week it is secondary, last 4 weeks.Make in combination
With in treatment group, antibody 442S1 and Cetuximab are administered in the tail vein of mouse one week with the dosage of 5mg/kg body weight
It is secondary, last 4 weeks.Then, antibody is not given lasts one week.Measure tumor size is secondary within one week.Calculating antibody is given or combined
Gross tumor volume after giving.As a result it is shown in Fig. 9, wherein down arrow (↓) represents the time of injection cancer cell, and * * * tables
Show figure base multiple comparative test (Tukey ' the s multiple after one-way analysis of variance (one-way ANOVA)
Comparison test) result (p<0.001).
Referring to Fig. 9, in being applied in combination in treatment group for antibody 442S1 and Cetuximab, gross tumor volume is from initial dose
It is average about 68mm that stage, which reduces and at the end of test,3(n=10/ groups).Thus, it is found that the antibody of selection and western appropriate former times
The combination medicine-feeding of monoclonal antibody improves anticancer efficiency.
The improvement of the anticarcinogen drug resistance of the anti-ErbB3 antibody of embodiment 5.
1. the improvement of the taxol resistance in breast cancer
Due to the activation of ErbB3 signal transduction pathways, taxol can be made in the presence of HRG in breast cancer cell line ZR-75-
Apoptic effects in 30 decline (Wang S. etc., Oncogene, 29,4225-4236,2010).Investigated to assess sieve
The antibody of choosing improves the drug resistance of the taxol as anticarcinogen and assigns the ability of anticancer effect.
Make about 1x104Individual ZR-75-30 cells (American Type Culture Collection) are inoculated on plate
And in 5%CO2Under the conditions of, at 37 DEG C in the culture mediums of RPMI 1640 (Invitrogen) including 10% (v/v) FBS
Cultivate about 24 hours.Then culture medium is changed into fresh culture medium (the addition 100ng/mL including 0.1% (v/v) FBS
HRG), and in 5%CO2Under the conditions of, carry out further cultivate at 37 DEG C and last about 24 hours.Add 10nM Japanese yew
Alcohol (Bristol-MyersSquibb) and 25 μ g/mL antibody 442S1 are to the cell cultivated and in 5%CO2Under the conditions of,
Cultivated at 37 DEG C about 72 hours.The cell of culture is collected, and uses the substrate assay method (Promega) of Caspase-3/7
Determine the activity of Caspase-3/7 as apoptotic marker.The work of Caspase-3/7 measured is shown in Figure 10
Property, wherein RLU represents relative light units, and * * represent t- assays (p<0.01).
Referring to Figure 10, taxol reduces the activity of Caspase-3/7, but with being used individually (n=3) phase with taxol
Than taxol and antibody 442S1 combined therapy improve the activity of Caspase-3/7.Thus, it is found that can depositing in HRG
Make the apoptic effects of taxol reduce under, but recovered by giving antibody 442S1.
2. the Cetuximab drug resistance improvement in colorectal cancer
Due to the activation of ErbB3 signal transduction pathways, Cetuximab effectively suppresses in DiFi colorectal cancer cells
Cancer cell multiplication, but its efficiency is lost in the presence of HRG.Investigated and overcome with assessing the antibody of screening to Cetuximab
Drug resistance ability and assign cancer cell multiplication inhibition ability.
Specifically, by DiFi colon cancer cells including antibiotic (Pen .- Strep, Invitrogen) and 10%
Cultivated in FBS RPMI-1640 culture mediums (Invitrogen).Make about 1x104Individual DiFi cells are inoculated on 96 orifice plates simultaneously
And in 5%CO2Under the conditions of, cultivated at 37 DEG C about 24 hours.By Cetuximab and anti-ErbB3 antibody system with 200 μ g/
ML isoconcentration is mixed to obtain Cetuximab/anti-ErbB3 antibody-solutions, then by its HRG with equivalent
(40ng/mL) is mixed.Cetuximab/anti-ErbB3 antibody/HRG solution is applied to 96 orifice plates and in 5%CO2Condition
Under, cultivated at 37 DEG C about 72 hours.The cell cultivated in the case of no antibody and HRG is used as negative control group.Profit
With the number of CellTiter-Glo luminescent cell viabilities analytic approach (Promega) measure living cells.Based on the result measured come
Calculate cell proliferation rate.As a result it is shown in Figure 11, wherein * * * represent t- assays (p<0.001).
Referring to Figure 11, make the cell inhibitory effect effect of Cetuximab reduce in the presence of HRG, but it is western appropriate in receiving
Recover in the treatment group of the combination of former times monoclonal antibody and 442S1 antibody.Thus, it is found that it can make in the presence of HRG, i.e. ErbB3 parts
The cell inhibitory effect effect of Cetuximab is reduced, but HRG-ErbB3 can be blockaded by 442S1 antibody and summons approach and extensive
It is multiple.
3. the improvement in Cetuximab patience heteroplastic transplantation model to Cetuximab drug resistance
FaDu human taus cervix carcinoma cells (Shanghai Institutes of Biological Sciences) are existed
Cultivated in EMEM culture mediums (Hyclone), EMEM culture mediums include 10%FBS (Invitrogen), 0.01mM NEAA (Non-
Essential Amino Acid, Hyclone) and 2mM Glus (Invitrogen).Make about 5x106Individual FaDu cancers
Cell is suspended in 100PBS in, be then subcutaneously injected to female NOD SCID mices (HFK Bio-Technology
Co., Ltd.) subventral space in.The weight of one week measure mouse is secondary, and utilizes " 0.5a x b2" equation calculate
Gross tumor volume, wherein a and major diameter and minor axis that b is respectively tumour.Gross tumor volume reaches about after cancer cell inoculation 8 days
165mm3When, randomly choose mouse.PBS (negative control group) or Cetuximab are administered to respectively with the dosage of 5mg/kg weight
Group mouse tail vein in one week it is secondary, last 6.5 weeks.When it is no maintenance Cetuximab tumor growth inhibitory effect so that
Gross tumor volume increases to about 840mm3When, from each group randomly choose 10 mouse, and by 5mg/kg Cetuximab,
10mg/kg antibody 442S1 or 5mg/kg Cetuximab and 10mg/kg antibody 442S1 combination medicine-feeding are to mouse one
Zhou Erci, last 2 weeks.Measure gross tumor volume is secondary within one week.As a result it is shown in Figure 12.
Referring to Figure 12, find receiving the treatment group of antibody 442S1 independent or antibody 442S1 and Cetuximab combination
In, compared with receiving the single treatment group of Cetuximab, it was observed that significant tumor inhibitory effect, represents that antibody 442S1 can
To overcome the drug resistance to Cetuximab and suppress tumour growth.
As described above, according to one or more illustrated embodiments, there is provided the antibody of specific binding ErbB3 a kind of or its
Antigen-binding fragment, and application thereof.Specific binding ErbB3 antibody or its antigen-binding fragment is effectively used for preventing
Or the disease that activation or overexpression of the treatment to ErbB3 albumen are related.
It should be understood that illustrated embodiment specifically described herein should be regarded as merely descriptive meaning and not in order to
Limitation.The explanation of feature or aspect in each illustrated embodiment should normally think can be used for its in other embodiment
His similar feature or aspect.
Although with reference to the accompanying drawings of one or more illustrated embodiments, those skilled in the art will appreciate that
In the case where not departing from the spirit and scope for the present inventive concept being defined by the following claims, various forms can be made
And the change of details.
<110>Co., Ltd. pear tree Ai Bosi
<120>Specifically bind ERBB3 antibody and application thereof
<130> PX-53072-PCT
<160> 101
<170> KopatentIn 2.0
<210> 1
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442P weight chain variable district
<400> 1
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Asp Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Leu His Met Gly Pro Glu Gly Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 2
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442S1 weight chain variable district
<400> 2
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asp Leu Asp Ser Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Leu His Met Gly Pro Glu Gly Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 3
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442S2 weight chain variable district
<400> 3
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Asp Ser Gly Ser Thr Asp Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Leu His Met Gly Pro Glu Gly Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 4
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442S4 weight chain variable district
<400> 4
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Glu Pro Asp Phe Gly Ser Ser Tyr Tyr Ala Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Leu His Met Gly Pro Glu Gly Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 5
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442S5 weight chain variable district
<400> 5
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ile Ile Glu Pro Asp Ser Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Leu His Met Gly Pro Glu Gly Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 6
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442S6 weight chain variable district
<400> 6
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Asp Ser Gly Ser Thr Asp Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg His Met Trp Pro Glu Gly Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 7
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442S9 weight chain variable district
<400> 7
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Asp Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg His Met Trp Pro Glu Gly Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 8
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442S10 weight chain variable district
<400> 8
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Asp Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg His Met Trp Pro Glu Gly Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 9
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442M3 weight chain variable district
<400> 9
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Asp Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg His Met Trp Pro Glu Gly Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 10
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442M4 weight chain variable district
<400> 10
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asp Leu Asp Ser Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Leu His Met Gly Pro Glu Gly Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 11
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442M5 weight chain variable district
<400> 11
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asp Leu Asp Ser Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Leu His Met Gly Pro Glu Gly Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 12
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442M6 weight chain variable district
<400> 12
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Glu Pro Asp Ser Gly Ser Thr Asp Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg His Met Trp Pro Glu Gly Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 13
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442M7 weight chain variable district
<400> 13
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Glu Pro Asp Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Gln Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Leu His Met Gly Pro Glu Gly Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 14
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442M8 weight chain variable district
<400> 14
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Asp Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Leu His Met Gly Pro Glu Gly Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 15
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442M10 weight chain variable district
<400> 15
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Asp Ser Gly Ser Thr Asp Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Leu His Met Trp Pro Glu Gly Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 16
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442M11 weight chain variable district
<400> 16
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Glu Pro Asp Tyr Gly Ser Thr Leu Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Leu His Met Gly Pro Glu Gly Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 17
<211> 127
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 472P weight chain variable district
<400> 17
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Tyr Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Pro Ser Trp Cys Leu Gln Asp Leu Cys Tyr Tyr Ala Asp
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 18
<211> 127
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 472S1 weight chain variable district
<400> 18
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Trp Tyr
20 25 30
Asp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Tyr Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Pro Ser Trp Cys Leu Gln Asp Leu Cys Tyr Tyr Ala Asp
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 19
<211> 127
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 472S2 weight chain variable district
<400> 19
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Trp Tyr
20 25 30
Asp Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Tyr Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Pro Ser Trp Cys Leu Gln Asp Leu Cys Tyr Tyr Ala Asp
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 20
<211> 127
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 472S3 weight chain variable district
<400> 20
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Trp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Tyr Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Pro Ser Trp Cys Leu Gln Asp Leu Cys Tyr Tyr Ala Asp
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 21
<211> 127
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 472S4 weight chain variable district
<400> 21
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Trp Tyr
20 25 30
Asp Ile Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Tyr Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Pro Ser Trp Cys Leu Gln Asp Leu Cys Tyr Tyr Ala Asp
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 22
<211> 127
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 472M1 weight chain variable district
<400> 22
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Trp Tyr
20 25 30
Asp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Tyr Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Pro Ser Trp Cys Leu Gln Asp Leu Cys Tyr Tyr Ala Asp
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 23
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 451P weight chain variable district
<400> 23
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Tyr Tyr Asp Ser Gly Ser Ile Tyr Tyr Ala Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Leu Phe Val Ser Asp Ser Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 24
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 451M1 weight chain variable district
<400> 24
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Tyr Tyr Asp Ser Gly Ser Ile Tyr Tyr Ala Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Leu Phe Met Ser Asp Ser Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 25
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 451M2 weight chain variable district
<400> 25
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Tyr Tyr Asp Ser Gly Ser Ile Tyr Tyr Ala Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Leu Phe Ala Ser Asp Ser Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 26
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 451M3 weight chain variable district
<400> 26
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Tyr Tyr Asp Ser Gly Ser Ile Tyr Tyr Ala Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Leu Phe Ala Ser Asp Ser Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 27
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 451M4 weight chain variable district
<400> 27
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Tyr Tyr Asp Ser Gly Ser Ile Tyr Tyr Ala Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Leu Phe Ala Ser Asp Ser Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 28
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 451M5 weight chain variable district
<400> 28
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Tyr Tyr Asp Ser Gly Ser Ile Tyr Tyr Ala Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Leu Phe Glu Ser Asp Ser Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 29
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 451M6 weight chain variable district
<400> 29
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Tyr Tyr Asp Ser Gly Ser Ile Tyr Tyr Ala Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Leu Phe Glu Ser Asp Ser Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 30
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 451M7 weight chain variable district
<400> 30
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Tyr Tyr Asp Ser Gly Ser Ile Tyr Tyr Ala Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Leu Phe Glu Ser Asp Ser Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 31
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442P light chain variable district
<400> 31
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Ser Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 32
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442S1 light chain variable district
<400> 32
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Gly Trp Asp Thr Ser Leu
85 90 95
Ser Gly His Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 33
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442S2 light chain variable district
<400> 33
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Ser Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 34
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442S4 light chain variable district
<400> 34
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Ser Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 35
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442S5 light chain variable district
<400> 35
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Ser Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 36
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442S6 light chain variable district
<400> 36
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Gly Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Asn Trp Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Ser Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 37
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442S9 light chain variable district
<400> 37
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Gly Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Ser Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 38
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442S10 light chain variable district
<400> 38
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Ser Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 39
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442M3 light chain variable district
<400> 39
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Gly Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Asn Trp Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Ser Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 40
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442M4 light chain variable district
<400> 40
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Val Gly Trp Asp Ser Ser Leu
85 90 95
Tyr Gly His Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 41
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442M5 light chain variable district
<400> 41
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys His Ala Trp Asp Ser Ser Leu
85 90 95
Trp Gly Asp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 42
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442M6 light chain variable district
<400> 42
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Gly Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Asn Trp Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Ser Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 43
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442M7 light chain variable district
<400> 43
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Ser Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 44
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442M8 light chain variable district
<400> 44
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys His Ala Trp Asp Ser Ser Leu
85 90 95
Tyr Val Asp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 45
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442M10 light chain variable district
<400> 45
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Asn Phe Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Ser Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 46
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 442M11 light chain variable district
<400> 46
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys His Ala Trp Asp Ser Ser Leu
85 90 95
Ser Gly Asp Phe Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 47
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 472P light chain variable district
<400> 47
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 48
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 472S1 light chain variable district
<400> 48
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 49
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 472S2 light chain variable district
<400> 49
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 50
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 472S3 light chain variable district
<400> 50
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 51
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 472S4 light chain variable district
<400> 51
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 52
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 472M1 light chain variable district
<400> 52
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 53
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 451P light chain variable district
<400> 53
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Pro Ser Asn Ile Gly Asn Asn
20 25 30
Ser Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Ala Ser Leu
85 90 95
Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 54
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 451M1 light chain variable district
<400> 54
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Pro Ser Asn Ile Gly Asn Asn
20 25 30
Ser Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Ala Ser Leu
85 90 95
Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 55
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 451M2 light chain variable district
<400> 55
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Pro Ser Asn Ile Gly Asn Asn
20 25 30
Ser Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Ala Ser Leu
85 90 95
Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 56
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 451M3 light chain variable district
<400> 56
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Pro Ser Asn Ile Gly Asn Asn
20 25 30
Ser Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Ala Ser Leu
85 90 95
Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 57
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 451M4 light chain variable district
<400> 57
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Pro Ser Asn Ile Gly Asn Asn
20 25 30
Ser Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Ala Ser Leu
85 90 95
Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 58
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 451M5 light chain variable district
<400> 58
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Pro Ser Asn Ile Gly Asn Asn
20 25 30
Ser Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Ala Ser Leu
85 90 95
Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 59
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 451M6 light chain variable district
<400> 59
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Pro Ser Asn Ile Gly Asn Asn
20 25 30
Ser Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Ala Ser Leu
85 90 95
Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 60
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Antibody 451M7 light chain variable district
<400> 60
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Pro Ser Asn Ile Gly Asn Asn
20 25 30
Ser Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Ala Ser Leu
85 90 95
Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 61
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR1
<400> 61
Asp Tyr Asp Met Ser
1 5
<210> 62
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR1
<400> 62
Trp Tyr Asp Met Thr
1 5
<210> 63
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR1
<400> 63
Trp Tyr Asp Leu Ala
1 5
<210> 64
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR1
<400> 64
Trp Tyr Asp Met Ser
1 5
<210> 65
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR1
<400> 65
Trp Tyr Asp Ile Ala
1 5
<210> 66
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR1
<400> 66
Trp Tyr Asp Leu Ser
1 5
<210> 67
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR1
<400> 67
His Tyr Asp Met Ser
1 5
<210> 68
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR1
<400> 68
Tyr Tyr Asp Met Ser
1 5
<210> 69
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR2
<400> 69
Ser Ile Tyr Pro Asp Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val Gln
1 5 10 15
Gly
<210> 70
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR2
<400> 70
Thr Ile Asp Leu Asp Ser Gly Ser Ile Tyr Tyr Ala Asp Ser Val Gln
1 5 10 15
Gly
<210> 71
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR2
<400> 71
Ser Ile Tyr Pro Asp Ser Gly Ser Thr Asp Tyr Ala Asp Ser Val Gln
1 5 10 15
Gly
<210> 72
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR2
<400> 72
Ser Ile Glu Pro Asp Phe Gly Ser Ser Tyr Tyr Ala Asp Ser Val Arg
1 5 10 15
Gly
<210> 73
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR2
<400> 73
Ile Ile Glu Pro Asp Ser Gly Ser Ile Tyr Tyr Ala Asp Ser Val Gln
1 5 10 15
Gly
<210> 74
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR2
<400> 74
Ser Ile Glu Pro Asp Ser Gly Ser Thr Asp Tyr Ala Asp Ser Val Gln
1 5 10 15
Gly
<210> 75
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR2
<400> 75
Thr Ile Glu Pro Asp Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val Gln
1 5 10 15
Ser
<210> 76
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR2
<400> 76
Gly Ile Ser Tyr Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 77
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR2
<400> 77
Ala Ile Tyr Tyr Asp Ser Gly Ser Ile Tyr Tyr Ala Asp Ser Ala Lys
1 5 10 15
Gly
<210> 78
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR3
<400> 78
Asp Leu His Met Gly Pro Glu Gly Pro Phe Asp Tyr
1 5 10
<210> 79
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR3
<400> 79
Asp Arg His Met Trp Pro Glu Gly Pro Phe Asp Tyr
1 5 10
<210> 80
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR3
<400> 80
Asp Leu His Met Trp Pro Glu Gly Pro Phe Asp Tyr
1 5 10
<210> 81
<211> 18
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR3
<400> 81
Asp Pro Ser Trp Cys Leu Gln Asp Leu Cys Tyr Tyr Ala Asp Gly Met
1 5 10 15
Asp Val
<210> 82
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR3
<400> 82
Asp Arg Leu Phe Val Ser Asp Ser Thr Phe Asp Tyr
1 5 10
<210> 83
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR3
<400> 83
Asp Arg Leu Phe Met Ser Asp Ser Thr Phe Asp Tyr
1 5 10
<210> 84
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR3
<400> 84
Asp Arg Leu Phe Ala Ser Asp Ser Thr Phe Asp Tyr
1 5 10
<210> 85
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Heavy chain CDR3
<400> 85
Asp Arg Leu Phe Glu Ser Asp Ser Thr Phe Asp Tyr
1 5 10
<210> 86
<211> 13
<212> PRT
<213>Artificial sequence
<220>
<223>Light chain CDR1
<400> 86
Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Ser Val Ser
1 5 10
<210> 87
<211> 13
<212> PRT
<213>Artificial sequence
<220>
<223>Light chain CDR1
<400> 87
Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Ser Gly Ser
1 5 10
<210> 88
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Light chain CDR2
<400> 88
Ser Asp Asn His Arg Pro Ser
1 5
<210> 89
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Light chain CDR2
<400> 89
Ala Asp Asn Trp Arg Pro Ser
1 5
<210> 90
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Light chain CDR2
<400> 90
Ala Asp Asn His Arg Pro Ser
1 5
<210> 91
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Light chain CDR2
<400> 91
Ala Asp Asn Phe Arg Pro Ser
1 5
<210> 92
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Light chain CDR2
<400> 92
Ala Asp Ser Asn Arg Pro Ser
1 5
<210> 93
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Light chain CDR2
<400> 93
Tyr Asp Ser His Arg Pro Ser
1 5
<210> 94
<211> 11
<212> PRT
<213>Artificial sequence
<220>
<223>Light chain CDR3
<400> 94
Ala Ala Trp Asp Ser Ser Leu Ser Gly Tyr Val
1 5 10
<210> 95
<211> 11
<212> PRT
<213>Artificial sequence
<220>
<223>Light chain CDR3
<400> 95
Gln Gly Trp Asp Thr Ser Leu Ser Gly His Val
1 5 10
<210> 96
<211> 11
<212> PRT
<213>Artificial sequence
<220>
<223>Light chain CDR3
<400> 96
Val Gly Trp Asp Ser Ser Leu Tyr Gly His Val
1 5 10
<210> 97
<211> 11
<212> PRT
<213>Artificial sequence
<220>
<223>Light chain CDR3
<400> 97
His Ala Trp Asp Ser Ser Leu Trp Gly Asp Val
1 5 10
<210> 98
<211> 11
<212> PRT
<213>Artificial sequence
<220>
<223>Light chain CDR3
<400> 98
His Ala Trp Asp Ser Ser Leu Tyr Val Asp Val
1 5 10
<210> 99
<211> 11
<212> PRT
<213>Artificial sequence
<220>
<223>Light chain CDR3
<400> 99
His Ala Trp Asp Ser Ser Leu Ser Gly Asp Phe
1 5 10
<210> 100
<211> 11
<212> PRT
<213>Artificial sequence
<220>
<223>Light chain CDR3
<400> 100
Gly Ser Trp Asp Tyr Ser Leu Ser Gly Tyr Val
1 5 10
<210> 101
<211> 11
<212> PRT
<213>Artificial sequence
<220>
<223>Light chain CDR3
<400> 101
Gly Ser Trp Asp Ala Ser Leu Asn Gly Tyr Val
1 5 10
Claims (22)
1. a kind of specific binding ErbB3 antibody or its antigen-binding fragment, it is included：
Weight chain variable district, it includes being selected from by sequence number：At least one amino acid sequence in the group of 61 to 85 compositions；
Light chain variable district, it includes being selected from by sequence number：At least one amino acid sequence in the group of 86 to 101 compositions；Or
The weight chain variable district and the light chain variable district.
2. antibody according to claim 1 or antigen-binding fragment, wherein the weight chain variable district includes：
Complementarity-determining region-H1 (CDR-H1), it includes being selected from by sequence number：Amino acid sequence in the group of 61 to 68 compositions；
CDR-H2, it includes being selected from sequence number：Amino acid sequence in 69 to 77；With
CDR-H3, it includes being selected from sequence number：Amino acid sequence in 78 to 85.
3. antibody according to claim 2 or antigen-binding fragment, it is selected from wherein the weight chain variable district further includes
By sequence number：Amino acid sequence in the group of 1 to 30 composition.
4. antibody according to claim 1 or antigen-binding fragment, wherein the light chain variable district includes：
CDR-L1, it includes being selected from by sequence number：Amino acid sequence in the group of 86 and 87 compositions；
CDR-L2, it includes being selected from by sequence number：Amino acid sequence in the group of 88 to 93 compositions；With
CDR-L3, it includes being selected from by sequence number：Amino acid sequence in the group of 94 to 101 compositions.
5. antibody according to claim 4 or antigen-binding fragment, it is selected from wherein the light chain variable district further includes
By sequence number：Amino acid sequence in the group of 31 to 60 compositions.
6. antibody according to claim 1 or antigen-binding fragment, it is selected from wherein the weight chain variable district includes by complementation
Property determine any one of group of area-H1 (CDR-H1), CDR-H2 and CDR-H3 compositions, it includes the amino acid listed in following table
Sequence：
<Table 5>
7. antibody according to claim 1 or antigen-binding fragment, it is selected from wherein the light chain variable district includes by complementation
Property determine any one of group of area-L1 (CDR-L1), CDR-L2 and CDR-L3 compositions, it includes the amino acid listed in following table
Sequence：
<Table 6>
8. antibody according to claim 1 or antigen-binding fragment, wherein the antibody or antigen-binding fragment suppression
The combination of material of ErbB3 albumen processed and specific binding ErbB3 albumen, the dimerization of ErbB1 albumen and ErbB3 albumen, ErbB2
Albumen and dimerization, ErbB3 or the Akt phosphorylation of ErbB3 albumen or its combine.
9. antibody according to claim 8 or antigen-binding fragment, wherein specifically binding the material of the ErbB3 albumen
For heregulin (HRG).
10. antibody according to claim 1 or antigen-binding fragment, wherein the antibody be IgA, IgD, IgE, IgG or
IgM；Wherein the body is monoclonal antibody or polyclonal antibody；Or wherein described antigen-binding fragment be scFv,
(scFv)2、Fv、Fab、Fab'、F(ab')2Or its combination；Or wherein described antibody or its antigen-binding fragment pass through it is conjugated
Or combination, candy base, label attachment or its combination are modified.
11. a kind of pharmaceutical composition for being used to preventing or treating the disease related to the activation of ErbB3 albumen or overexpression, described
Pharmaceutical composition includes antibody according to any one of claim 1 to 10 or antigen-binding fragment.
12. pharmaceutical composition according to claim 11, wherein the disease that activation or overexpression to ErbB3 albumen is related
For cancer.
13. pharmaceutical composition according to claim 12, wherein the cancer is selected from consisting of the following group：Breast cancer, skin
Skin cancer, incidence cancer, cancer of pancreas, lung cancer, colon cancer, colorectal cancer, stomach cancer, oophoroma, prostate cancer, carcinoma of urinary bladder, uterus
Cancer, liver cancer, renal cancer, clear cell sarcoma, melanoma, myelencephalon tumour, the cancer of the brain, thymoma, celiothelioma, cancer of the esophagus, courage
Road Ai, testicular cancers, embryo cancer, thyroid cancer, parathyroid carcinoma, cervix cancer, carcinoma of endometrium, lymthoma, myeloproliferative disorder
Syndrome (MDS), myelofibrosis, acute leukemia, chronic leukemia, Huppert's disease, Hodgkin's disease, endocrine cancer
And sarcoma.
14. pharmaceutical composition according to claim 11, it further includes anticarcinogen.
15. pharmaceutical composition according to claim 14, wherein the anticarcinogen is Cetuximab, Victibix, strategic point
Lip river is for Buddhist nun, Gefitinib, Herceptin, T-DM1, handkerchief trastuzumab, Lapatinib, taxol, TAM, cis-platinum, anti-
CTLA-4 antibody, anti-PD-1 antibody, anti-PDL-1 antibody, 5 FU 5 fluorouracil (5FU), gemcitabine or its combination.
16. pharmaceutical composition according to claim 14, wherein described pharmaceutical composition further include single composition
Or discrete sets compound.
17. it is a kind of prevent or treatment individual in the method for activation to ErbB3 albumen or the related disease of overexpression, methods described
Comprising antibody according to any one of claim 1 to 10 or antigen-binding fragment are delivered medicine into the individual.
18. according to the method for claim 17, it further includes anticarcinogen delivering medicine to the individual.
19. according to the method for claim 18, wherein by the anticarcinogen and according to any one of claim 1 to 10 institute
The antibody or antigen-binding fragment stated simultaneously, dividually or are one after the other administered.
20. according to the method for claim 18, wherein by the antibody, its antigen-binding fragment, the anticarcinogen or its
Combination delivers medicine to described by oral, intravenous, intramuscular, percutaneous, mucous membrane, intranasal, tracheal strips, subcutaneous administration and combinations thereof
Body.
21. according to the method for claim 18, wherein by the antibody, its antigen-binding fragment, the anticarcinogen or its
Combination capapie or is partly administered.
22. it is a kind of prevent or treatment individual in cancer drug drug resistance method, methods described include will according to claim 1 to
Antibody or antigen-binding fragment any one of 10 deliver medicine to the individual.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011145330.1A CN112472804A (en) | 2015-12-07 | 2016-11-02 | Antibodies that specifically bind to ERBB3 and uses thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020150173281A KR101746152B1 (en) | 2015-12-07 | 2015-12-07 | Antibody specifically binding to ErbB3 and use thereof |
| KR10-2015-0173281 | 2015-12-07 | ||
| PCT/KR2016/012545 WO2017099362A1 (en) | 2015-12-07 | 2016-11-02 | Antibody specifically binding to erbb3 and use thereof |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011145330.1A Division CN112472804A (en) | 2015-12-07 | 2016-11-02 | Antibodies that specifically bind to ERBB3 and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107683292A true CN107683292A (en) | 2018-02-09 |
| CN107683292B CN107683292B (en) | 2021-06-08 |
Family
ID=59013461
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011145330.1A Pending CN112472804A (en) | 2015-12-07 | 2016-11-02 | Antibodies that specifically bind to ERBB3 and uses thereof |
| CN201680021403.1A Active CN107683292B (en) | 2015-12-07 | 2016-11-02 | Antibodies that specifically bind to ERBB3 and uses thereof |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011145330.1A Pending CN112472804A (en) | 2015-12-07 | 2016-11-02 | Antibodies that specifically bind to ERBB3 and uses thereof |
Country Status (15)
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| US (1) | US10413607B2 (en) |
| EP (2) | EP3778647A1 (en) |
| JP (2) | JP6982574B2 (en) |
| KR (1) | KR101746152B1 (en) |
| CN (2) | CN112472804A (en) |
| AR (1) | AR107012A1 (en) |
| AU (1) | AU2016365506B2 (en) |
| BR (1) | BR112018006900A2 (en) |
| CA (1) | CA3000835C (en) |
| ES (1) | ES2891990T3 (en) |
| MX (1) | MX2018004228A (en) |
| PL (1) | PL3362480T3 (en) |
| RU (1) | RU2707121C9 (en) |
| TW (1) | TWI615406B (en) |
| WO (1) | WO2017099362A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3868782A1 (en) * | 2018-10-17 | 2021-08-25 | Good T Cells, Inc. | Binding molecule specific to lrig-1 protein, and use thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101674846A (en) * | 2007-02-16 | 2010-03-17 | 梅里麦克制药股份有限公司 | Antibodies against erbb3 and uses thereof |
| CN103917562A (en) * | 2011-09-30 | 2014-07-09 | 瑞泽恩制药公司 | Anti-ErbB3 antibodies and uses thereof |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR0173281B1 (en) | 1996-11-30 | 1999-02-18 | 양재신 | Lamp angle control device |
| CN102057054B (en) * | 2008-04-11 | 2015-06-10 | 梅里麦克制药股份有限公司 | Human serum albumin linkers and conjugates thereof |
| JP5677972B2 (en) | 2008-11-18 | 2015-02-25 | メリマック ファーマシューティカルズ インコーポレーティッド | Human serum albumin linker and its conjugates |
| SG183532A1 (en) * | 2010-03-11 | 2012-09-27 | Merrimack Pharmaceuticals Inc | Use of erbb3 inhibitors in the treatment of triple negative and basal-like breast cancers |
| ES2566602T3 (en) | 2010-04-09 | 2016-04-14 | Aveo Pharmaceuticals, Inc. | Anti-ErbB3 antibodies |
| PT2606070T (en) * | 2010-08-20 | 2017-03-31 | Novartis Ag | Antibodies for epidermal growth factor receptor 3 (her3) |
| JPWO2012176779A1 (en) * | 2011-06-20 | 2015-02-23 | 協和発酵キリン株式会社 | Anti-erbB3 antibody |
| US9273143B2 (en) | 2011-09-30 | 2016-03-01 | Regeneron Pharmaceuticals, Inc. | Methods and compositions comprising a combination of an anti-ErbB3 antibody and an anti-EGFR antibody |
| WO2015048008A2 (en) * | 2013-09-24 | 2015-04-02 | Medimmune, Llc | Binding molecules specific for her3 and uses thereof |
-
2015
- 2015-12-07 KR KR1020150173281A patent/KR101746152B1/en active IP Right Grant
-
2016
- 2016-11-02 AU AU2016365506A patent/AU2016365506B2/en active Active
- 2016-11-02 WO PCT/KR2016/012545 patent/WO2017099362A1/en active Application Filing
- 2016-11-02 US US15/563,227 patent/US10413607B2/en active Active
- 2016-11-02 CN CN202011145330.1A patent/CN112472804A/en active Pending
- 2016-11-02 PL PL16873228T patent/PL3362480T3/en unknown
- 2016-11-02 CN CN201680021403.1A patent/CN107683292B/en active Active
- 2016-11-02 EP EP20196712.2A patent/EP3778647A1/en active Pending
- 2016-11-02 ES ES16873228T patent/ES2891990T3/en active Active
- 2016-11-02 CA CA3000835A patent/CA3000835C/en active Active
- 2016-11-02 JP JP2018542089A patent/JP6982574B2/en active Active
- 2016-11-02 RU RU2018113269A patent/RU2707121C9/en active
- 2016-11-02 EP EP16873228.7A patent/EP3362480B1/en active Active
- 2016-11-02 BR BR112018006900-0A patent/BR112018006900A2/en active Search and Examination
- 2016-11-02 MX MX2018004228A patent/MX2018004228A/en unknown
- 2016-12-06 TW TW105140259A patent/TWI615406B/en active
- 2016-12-07 AR ARP160103758A patent/AR107012A1/en unknown
-
2020
- 2020-03-19 JP JP2020049129A patent/JP6989645B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101674846A (en) * | 2007-02-16 | 2010-03-17 | 梅里麦克制药股份有限公司 | Antibodies against erbb3 and uses thereof |
| CN103917562A (en) * | 2011-09-30 | 2014-07-09 | 瑞泽恩制药公司 | Anti-ErbB3 antibodies and uses thereof |
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| JINGCAO HUANG，等: "The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells", 《MOLECULAR CANCER》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| TW201726742A (en) | 2017-08-01 |
| KR101746152B1 (en) | 2017-06-13 |
| AU2016365506A9 (en) | 2018-11-01 |
| EP3362480B1 (en) | 2021-08-04 |
| RU2018113269A (en) | 2019-10-18 |
| CA3000835A1 (en) | 2017-06-15 |
| JP2020117512A (en) | 2020-08-06 |
| CA3000835C (en) | 2020-06-09 |
| EP3362480A4 (en) | 2019-06-05 |
| AU2016365506A1 (en) | 2018-04-12 |
| US10413607B2 (en) | 2019-09-17 |
| RU2707121C9 (en) | 2020-06-16 |
| EP3778647A1 (en) | 2021-02-17 |
| AR107012A1 (en) | 2018-03-14 |
| RU2707121C2 (en) | 2019-11-22 |
| CN107683292B (en) | 2021-06-08 |
| PL3362480T3 (en) | 2022-01-03 |
| MX2018004228A (en) | 2018-05-15 |
| CN112472804A (en) | 2021-03-12 |
| JP6989645B2 (en) | 2022-01-05 |
| JP2018536026A (en) | 2018-12-06 |
| BR112018006900A2 (en) | 2018-10-16 |
| TWI615406B (en) | 2018-02-21 |
| JP6982574B2 (en) | 2021-12-17 |
| RU2018113269A3 (en) | 2019-10-18 |
| EP3362480A1 (en) | 2018-08-22 |
| ES2891990T3 (en) | 2022-02-01 |
| WO2017099362A1 (en) | 2017-06-15 |
| US20180085455A1 (en) | 2018-03-29 |
| AU2016365506B2 (en) | 2019-06-20 |
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